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Abstract:

The present invention relates to compounds of Formula I and
pharmaceutically acceptable compositions thereof, useful as IRAK
inhibitors.

Claims:

1. A compound of formula I, ##STR00706## or a pharmaceutically
acceptable salt thereof, wherein: X is CR or N; A is O, S, SO2, SO,
--NRC(O), --NRSO2, or N(R); or A is absent; R3 is --R, halogen,
-haloalkyl, --OR, --SR, --CN, --NO2, --SO2R, --SOR, --C(O)R,
--CO2R, --C(O)N(R)2, --NRC(O)R, --NRC(O)N(R)2,
--NRSO2R, or --N(R)2; or when A is --NRC(O), --NRSO2, or
N(R); then R and R3, together with the atoms to which each is
attached, may form a 3-7 membered heterocylic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; each of which is optionally
substituted; X' is CR or N; Ring Z is a 3-7 membered heterocylic ring
having 1-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur; each
of which is optionally substituted; R1 is --R, halogen, -haloalkyl,
--OR, --SR, --CN, --NO2, --SO2R, --SOR, --C(O)R, --CO2R,
--C(O)N(R)2, --NRC(O)R, --NRC(O)N(R)2, --NRSO2R, or
--N(R)2; Ra is absent, --R, halogen, -haloalkyl, --OR, --SR,
--CN, --NO2, --SO2R, --SOR, --C(O)R, --CO2R,
--C(O)N(R)2, --NRC(O)R, --NRC(O)N(R)2, --NRSO2R, or
--N(R)2; Ring Y is an optionally substituted 5-6 membered monocyclic
heteroaryl ring having 2-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur; R2 is --R, halogen, -haloalkyl, --OR,
--SR, --CN, --NO2, --SO2R, --SOR, --C(O)R, --CO2R,
--C(O)N(R)2, --NRC(O)R, --NRC(O)N(R)2, --NRSO2R, or
--N(R)2; Rb is absent, --R, halogen, -haloalkyl, --OR, --SR,
--CN, --NO2, --SO2R, --SOR, --C(O)R, --CO2R,
--C(O)N(R)2, --NRC(O)R, --NRC(O)N(R)2, --NRSO2R, or
--N(R)2; each R is independently hydrogen, C1-6 aliphatic,
C3-10 aryl, a 3-8 membered saturated or partially unsaturated
carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; each of which is optionally
substituted; or two R groups on the same atom are taken together with the
atom to which they are attached to form a C3-10 aryl, a 3-8 membered
saturated or partially unsaturated carbocyclic ring, a 3-7 membered
heterocylic ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur; each of which is optionally substituted; wherein when X is N and
A is absent, then R3 is not H.

12. The compound of claim 1, of formula I-b, ##STR00726## or a
pharmaceutically acceptable salt thereof.

13. The compound of claim 1, of formula I-c, ##STR00727## or a
pharmaceutically acceptable salt thereof.

14. The compound of claim 1, selected from Table 1.

15. A pharmaceutical composition comprising a compound of claim 1, and a
pharmaceutically acceptable adjuvant, carrier, or vehicle.

16. A method for inhibiting IRAK, or a mutant thereof, activity in a
patient or in a biological sample, comprising the step of administering
to said patient or contacting said biological sample with a compound of
claim 1 or a physiologically acceptable salt thereof.

17. A method for treating an IRAK-mediated disorder in a patient in need
thereof, comprising the step of administering to said patient a compound
of claim 1.

19. A method for treating cancer in a subject, comprising the step of
administering to said subject a compound of claim 1 or a physiologically
acceptable salt thereof.

20. A process for manufacturing a compound of formula I according to
claim 1, comprising the steps of: reacting a compound of formula (A):
##STR00728## with ##STR00729## wherein X, Y, A, R, Ra, Rb,
R2 and R3 are as defined in claim 1; to provide a compound of
formula (B): ##STR00730## and reacting the compound of formula (B) with
##STR00731## wherein Z and R1 are as defined in claim 1; to
provide a compound of formula I of claim 1.

Description:

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application
62/082,231, filed on Nov. 20, 2014, the contents of which are
incorporated in its entirety by reference.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention provides for compounds of Formula (I) as IRAK
inhibitors and their use in the treatment of cancer, and other diseases
related to IRAK overexpression, including rheumatoid arthritis, systemic
lupus erythematosus or lupus nephritis.

BACKGROUND OF THE INVENTION

[0003] Kinases catalyze the phosphorylation of proteins, lipids, sugars,
nucleosides and other cellular metabolites and play key roles in all
aspects of eukaryotic cell physiology. Especially, protein kinases and
lipid kinases participate in the signaling events which control the
activation, growth, differentiation and survival of cells in response to
extracellular mediators or stimuli such as growth factors, cytokines or
chemokines. In general, protein kinases are classified in two groups,
those that preferentially phosphorylate tyrosine residues and those that
preferentially phosphorylate serine and/or threonine residues.

[0004] Kinases are important therapeutic targets for the development of
anti-inflammatory drugs (Cohen, 2009. Current Opinion in Cell Biology 21,
1-8), for example kinases that are involved in the orchestration of
adaptive and innate immune responses. Kinase targets of particular
interest are members of the IRAK family.

[0006] Mice that express a catalytically inactive mutant of IRAK4 instead
of the wild-type kinase are completely resistant to septic shock
triggered by several TLR agonists and are impaired in their response to
IL-1. Children who lack IRAK4 activity due to a genetic defect suffer
from recurring infection by pyogenic bacteria. It appears that
IRAK-dependent TLRs and IL-1Rs are vital for childhood immunity against
some pyogenic bacteria but play a redundant role in protective immunity
to most infections in adults. Therefore IRAK4 inhibitors may be useful
for the treatment of chronic inflammatory diseases in adults without
making them too susceptible to bacterial and viral infections (Cohen,
2009. Current Opinion in Cell Biology 21, 1-8). Potent IRAK4 inhibitors
have been developed (Buckley et al., 2008. Bioorg Med Chem Lett.
18(12):3656-60). IRAK1 is essential for the TLR7-mediated and
TLR9-mediated activation of IRF7 and the production of interferon-alpha
(IFN-α) suggesting that IRAK1 inhibitors may be useful for the
treatment of Systemic lupus erythematosus (SLE). IRAK2 is activated
downstream of IRAK4 and plays a role in proinflammatory cytokine
production. Therefore IRAK2 inhibitors may be useful for inflammatory
diseases.

SUMMARY OF THE INVENTION

[0007] In one aspect, the invention provides compounds of Formula (I):

[0008] In another aspect, the invention provides compounds of Formula (I)
which are suitable for the treatment and/or prevention of disorders
related to IRAK. In another aspect, the invention provides compounds
which are able to modulate, especially inhibit the activity or function
of IRAK in disease states in mammals, especially in humans.

[0010] According to another aspect, the present invention provides
compounds of Formula (I) which are selective for IRAK-4 and/or IRAK-1.

[0011] According to another aspect, the present invention provides
compounds of Formula (I) which are selective for IRAK-4 and IRAK-1.

[0012] According to another aspect the invention provides a kit or a set
comprising at least one compound of Formula (I), preferably in
combination with immunomodulating agents.

[0013] Preferably, the kit consists of separate packs of:

(a) an effective amount of a compound of the formula (I) and/or
pharmaceutically usable derivatives, solvates, salts, hydrates and
stereoisomers thereof, including mixtures thereof in all ratios, and (b)
an effective amount of a further medicament active ingredient.

[0014] According to another aspect the invention provides a process for
the synthesis of compounds of Formulae (I).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

1. General Description of Compounds of the Invention

[0015] In certain aspects, the present invention provides for inhibitors
of IRAK. In some embodiments, such compounds include those of the
formulae described herein, or a pharmaceutically acceptable salt thereof,
wherein each variable is as defined and described herein.

2. Compounds and Definitions

[0016] Compounds of this invention include those described generally
above, and are further illustrated by the classes, subclasses, and
species disclosed herein. As used herein, the following definitions shall
apply unless otherwise indicated. For purposes of this invention, the
chemical elements are identified in accordance with the Periodic Table of
the Elements, CAS version, Handbook of Chemistry and Physics, 75th
Ed. Additionally, general principles of organic chemistry are described
in "Organic Chemistry", Thomas Sorrell, University Science Books,
Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed.,
Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the
entire contents of which are hereby incorporated by reference.

[0017] The term "aliphatic" or "aliphatic group", as used herein, means a
straight-chain (i.e., unbranched) or branched, substituted or
unsubstituted hydrocarbon chain that is completely saturated or that
contains one or more units of unsaturation, or a monocyclic hydrocarbon
or bicyclic hydrocarbon that is completely saturated or that contains one
or more units of unsaturation, but which is not aromatic (also referred
to herein as "carbocycle" "cycloaliphatic" or "cycloalkyl"), that has a
single point of attachment to the rest of the molecule. Unless otherwise
specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some
embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In
other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms.
In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon
atoms, and in yet other embodiments, aliphatic groups contain 1-2
aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or
"carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6
hydrocarbon that is completely saturated or that contains one or more
units of unsaturation, but which is not aromatic, that has a single point
of attachment to the rest of the molecule. Exemplary aliphatic groups are
linear or branched, substituted or unsubstituted C1-C8 alkyl,
C2-C8 alkenyl, C2-C8 alkynyl groups and hybrids
thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or
(cycloalkyl)alkenyl.

[0019] The term "lower haloalkyl" refers to a C1-4 straight or
branched alkyl group that is substituted with one or more halogen atoms.

[0020] The term "heteroatom" means one or more of oxygen, sulfur,
nitrogen, or phosphorus (including, any oxidized form of nitrogen,
sulfur, or phosphorus; the quaternized form of any basic nitrogen or; a
substitutable nitrogen of a heterocyclic ring, for example N (as in
3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in
N-substituted pyrrolidinyl)).

[0021] The term "unsaturated", as used herein, means that a moiety has one
or more units of unsaturation.

[0022] As used herein, the term "bivalent C1-8 (or C1-6)
saturated or unsaturated, straight or branched, hydrocarbon chain",
refers to bivalent alkylene, alkenylene, and alkynylene chains that are
straight or branched as defined herein.

[0023] The term "alkylene" refers to a bivalent alkyl group. An "alkylene
chain" is a polymethylene group, i.e., --(CH2)n--, wherein n is
a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3,
from 1 to 2, or from 2 to 3. A substituted alkylene chain is a
polymethylene group in which one or more methylene hydrogen atoms are
replaced with a substituent. Suitable substituents include those
described below for a substituted aliphatic group.

[0024] The term "alkenylene" refers to a bivalent alkenyl group. A
substituted alkenylene chain is a polymethylene group containing at least
one double bond in which one or more hydrogen atoms are replaced with a
substituent. Suitable substituents include those described below for a
substituted aliphatic group.

[0025] The term "halogen" means F, Cl, Br, or I.

[0026] The term "aryl" used alone or as part of a larger moiety as in
"aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and
bicyclic ring systems having a total of five to fourteen ring members,
wherein at least one ring in the system is aromatic and wherein each ring
in the system contains three to seven ring members. The term "aryl" is
used interchangeably with the term "aryl ring". In certain embodiments of
the present invention, "aryl" refers to an aromatic ring system.
Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl and the
like, which optionally includes one or more substituents. Also included
within the scope of the term "aryl", as it is used herein, is a group in
which an aromatic ring is fused to one or more non-aromatic rings, such
as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or
tetrahydronaphthyl, and the like.

[0027] The terms "heteroaryl" and "heteroar-", used alone or as part of a
larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to
groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;
having 6, 10, or 14π electrons shared in a cyclic array; and having,
in addition to carbon atoms, from one to five heteroatoms. The term
"heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any
oxidized form of nitrogen or sulfur, and any quaternized form of a basic
nitrogen. Heteroaryl groups include, without limitation, thienyl,
furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,
oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,
naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-",
as used herein, also include groups in which a heteroaromatic ring is
fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where
the radical or point of attachment is on the heteroaromatic ring.
Nonlimiting examples include indolyl, isoindolyl, benzothienyl,
benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,
quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A
heteroaryl group is optionally mono- or bicyclic. The term "heteroaryl"
is used interchangeably with the terms "heteroaryl ring", "heteroaryl
group", or "heteroaromatic", any of which terms include rings that are
optionally substituted. The term "heteroaralkyl" refers to an alkyl group
substituted by a heteroaryl, wherein the alkyl and heteroaryl portions
independently are optionally substituted.

[0028] As used herein, the terms "heterocycle", "heterocyclyl",
"heterocyclic radical", and "heterocyclic ring" are used interchangeably
and refer to a stable 5- to 7-membered monocyclic or 7-10-membered
bicyclic heterocyclic moiety that is either saturated or partially
unsaturated, and having, in addition to carbon atoms, one or more,
preferably one to four, heteroatoms, as defined above. When used in
reference to a ring atom of a heterocycle, the term "nitrogen" includes a
substituted nitrogen. As an example, in a saturated or partially
unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or
nitrogen, the nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in
pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).

[0029] A heterocyclic ring can be attached to its pendant group at any
heteroatom or carbon atom that results in a stable structure and any of
the ring atoms can be optionally substituted. Examples of such saturated
or partially unsaturated heterocyclic radicals include, without
limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,
piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,
diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The
terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic
group", "heterocyclic moiety", and "heterocyclic radical", are used
interchangeably herein, and also include groups in which a heterocyclyl
ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,
such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or
tetrahydroquinolinyl, where the radical or point of attachment is on the
heterocyclyl ring. A heterocyclyl group is optionally mono- or bicyclic.
The term "heterocyclylalkyl" refers to an alkyl group substituted by a
heterocyclyl, wherein the alkyl and heterocyclyl portions independently
are optionally substituted.

[0030] As used herein, the term "partially unsaturated" refers to a ring
moiety that includes at least one double or triple bond. The term
"partially unsaturated" is intended to encompass rings having multiple
sites of unsaturation, but is not intended to include aryl or heteroaryl
moieties, as herein defined.

[0031] As described herein, certain compounds of the invention contain
"optionally substituted" moieties. In general, the term "substituted",
whether preceded by the term "optionally" or not, means that one or more
hydrogens of the designated moiety are replaced with a suitable
substituent. "Substituted" applies to one or more hydrogens that are
either explicit or implicit from the structure (e.g.,

##STR00002##

refers to at least

##STR00003##

and

##STR00004##

refers to at least

##STR00005##

Unless otherwise indicated, an "optionally substituted" group has a
suitable substituent at each substitutable position of the group, and
when more than one position in any given structure is substituted with
more than one substituent selected from a specified group, the
substituent is either the same or different at every position.
Combinations of substituents envisioned by this invention are preferably
those that result in the formation of stable or chemically feasible
compounds. The term "stable", as used herein, refers to compounds that
are not substantially altered when subjected to conditions to allow for
their production, detection, and, in certain embodiments, their recovery,
purification, and use for one or more of the purposes disclosed herein.

[0033] Suitable monovalent substituents on R.sup.∘ (or the
ring formed by taking two independent occurrences of R.sup.∘
together with their intervening atoms), are independently deuterium,
halogen, --(CH2)0-2R.sup.•, -(haloR.sup.•),
--(CH2)0-2OH, --(CH2)0-2OR.sup.•,
--(CH2)0-2CH(OR.sup.•)2; --O(haloR.sup.•),
--CN, --N3, --(CH2)0-2C(O)R.sup.•,
--(CH2)0-2C(O)OH, --(CH2)0-2C(O)OR.sup.•,
--(CH2)0-2SR.sup.•, --(CH2)0-2SH,
--(CH2)0-2NH2, --(CH2)0-2NHR.sup.•,
--(CH2)0-2NR.sup.•2, --NO2,
--SiR.sup.•3, --OSiR.sup.•3, --C(O)SR.sup.•,
--(C1-4 straight or branched alkylene)C(O)OR.sup.•, or
--SSR.sup.• wherein each R.sup.• is unsubstituted or where
preceded by "halo" is substituted only with one or more halogens, and is
independently selected from C1-4 aliphatic, --CH2Ph,
--O(CH2)0-1Ph, or a 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently selected
from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a
saturated carbon atom of R.sup.• include ═O and ═S.

[0034] Suitable divalent substituents on a saturated carbon atom of an
"optionally substituted" group include the following: ═O, ═S,
═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*,
═NR*, ═NOR*, --O(C(R*2))2-3O--, or
--S(C(R*2))2-3S--, wherein each independent occurrence of R* is
selected from hydrogen, C1-6 aliphatic which is substituted as
defined below, or an unsubstituted 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently selected
from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are
bound to vicinal substitutable carbons of an "optionally substituted"
group include: --O(CR*2)2-3O--, wherein each independent
occurrence of R* is selected from hydrogen, CI 6 aliphatic which is
optionally substituted as defined below, or an unsubstituted 5-6-membered
saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.

[0035] Suitable substituents on the aliphatic group of R* include halogen,
--R.sup.•, -(haloR.sup.•), --OH, --OR.sup.•,
--O(haloR.sup.•), --CN, --C(O)OH, --C(O)OR.sup.•, --NH2,
--NHR.sup.•, --NR.sup.•2, or --NO2, wherein each
R.sup.• is unsubstituted or where preceded by "halo" is substituted
only with one or more halogens, and is independently C1-4 aliphatic,
--CH2Ph, --O(CH2)0-1Ph, or a 5-6-membered saturated,
partially unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.

[0036] Suitable substituents on a substitutable nitrogen of an "optionally
substituted" group include --R.sup.†, --NR.sup.†2,
--C(O)R.sup.†, --C(O)OR.sup.†, --C(O)C(O)R.sup.†,
--C(O)CH2C(O)R.sup.†, --S(O)2R.sup.†,
--S(O)2NR.sup.†2, --C(S)NR.sup.†2,
--C(NH)NR.sup.†2, or
--N(R.sup.†)S(O)2R.sup.†; wherein each R.sup.†
is independently hydrogen, C1-6 aliphatic which is optionally
substituted as defined below, unsubstituted --OPh, or an unsubstituted
5-6-membered saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,
notwithstanding the definition above, two independent occurrences of
R.sup.†, taken together with their intervening atom(s) form an
unsubstituted 3-12-membered saturated, partially unsaturated, or aryl
mono- or bicyclic ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on the aliphatic group of R.sup.† are
independently halogen, --R.sup.•, -(haloR.sup.•), --OH,
--OR.sup.•, --O(haloR.sup.•), --CN, --C(O)OH,
--C(O)OR.sup.•, --NH2, --NHR.sup.•,
--NR.sup.•2, or --NO2, wherein each R.sup.• is
unsubstituted or where preceded by "halo" is substituted only with one or
more halogens, and is independently C1-4 aliphatic, --CH2Ph,
--O(CH2)0-1Ph, or a 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently selected
from nitrogen, oxygen, or sulfur.

[0038] In certain embodiments, the terms "optionally substituted",
"optionally substituted alkyl," "optionally substituted "optionally
substituted alkenyl," "optionally substituted alkynyl", "optionally
substituted carbocyclic," "optionally substituted aryl", "optionally
substituted heteroaryl," "optionally substituted heterocyclic," and any
other optionally substituted group as used herein, refer to groups that
are substituted or unsubstituted by independent replacement of one, two,
or three or more of the hydrogen atoms thereon with typical substituents
including, but not limited to:

[0056] Unless otherwise stated, structures depicted herein are also meant
to include all isomeric (e.g., enantiomeric, diastereomeric, and
geometric (or conformational)) forms of the structure; for example, the R
and S configurations for each asymmetric center, Z and E double bond
isomers, and Z and E conformational isomers. Therefore, single
stereochemical isomers as well as enantiomeric, diastereomeric, and
geometric (or conformational) mixtures of the present compounds are
within the scope of the invention. Unless otherwise stated, all
tautomeric forms of the compounds of the invention are within the scope
of the invention.

[0057] Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the presence of
one or more isotopically enriched atoms. For example, compounds having
the present structures including the replacement of hydrogen by deuterium
or tritium, or the replacement of a carbon by a 13C- or
14C-enriched carbon are within the scope of this invention. In some
embodiments, the group comprises one or more deuterium atoms.

[0058] There is furthermore intended that a compound of the formula I
includes isotope-labeled forms thereof. An isotope-labeled form of a
compound of the formula I is identical to this compound apart from the
fact that one or more atoms of the compound have been replaced by an atom
or atoms having an atomic mass or mass number which differs from the
atomic mass or mass number of the atom which usually occurs naturally.
Examples of isotopes which are readily commercially available and which
can be incorporated into a compound of the formula I by well-known
methods include isotopes of hydrogen, carbon, nitrogen, oxygen,
phos-phorus, fluo-rine and chlorine, for example 2H, 3H,
13C, 14C, 15N, 18O, 17O, 31P, 32P,
35S, 18F and 36CI, respectively. A compound of the formula
I, a prodrug, thereof or a pharmaceutically acceptable salt of either
which contains one or more of the above-mentioned isotopes and/or other
isotopes of other atoms is intended to be part of the present invention.
An isotope-labeled compound of the formula I can be used in a number of
beneficial ways. For example, an isotope-labeled compound of the formula
I into which, for example, a radioisotope, such as 3H or 14C,
has been incorporated, is suitable for medicament and/or substrate tissue
distribution assays. These radioisotopes, i.e. tritium (3H) and
carbon-14 (14C), are particularly preferred owing to simple
preparation and excellent detectability. Incorporation of heavier
isotopes, for example deuterium (2H), into a compound of the formula
I has therapeutic advantages owing to the higher metabolic stability of
this isotope-labeled compound. Higher metabolic stability translates
directly into an increased in vivo half-life or lower dosages, which
under most circumstances would represent a preferred embodiment of the
present invention. An isotope-labeled compound of the formula I can
usually be prepared by carrying out the procedures disclosed in the
synthesis schemes and the related description, in the example part and in
the preparation part in the present text, replacing a non-isotope-labeled
reactant by a readily available isotope-labeled reactant.

[0059] Deuterium (2H) can also be incorporated into a compound of the
formula I for the purpose in order to manipulate the oxidative metabolism
of the compound by way of the primary kinetic isotope effect. The primary
kinetic isotope effect is a change of the rate for a chemical reaction
that results from exchange of isotopic nuclei, which in turn is caused by
the change in ground state energies necessary for covalent bond formation
after this isotopic exchange.

[0060] Exchange of a heavier isotope usually results in a lowering of the
ground state energy for a chemical bond and thus causes a reduction in
the rate in rate-limiting bond breakage. If the bond breakage occurs in
or in the vicinity of a saddle-point region along the coordinate of a
multi-product reaction, the product distribution ratios can be altered
substantially. For explanation: if deuterium is bonded to a carbon atom
at a non-exchangeable position, rate differences of kM/kD=2-7
are typical. If this rate difference is successfully applied to a
com-pound of the formula I that is susceptible to oxidation, the profile
of this compound in vivo can be drastically modified and result in
improved pharmacokinetic properties.

[0061] When discovering and developing therapeutic agents, the person
skilled in the art is able to optimize pharmacokinetic parameters while
retaining desirable in vitro properties. It is reasonable to assume that
many compounds with poor pharmacokinetic profiles are susceptible to
oxidative metabolism. In vitro liver microsomal assays currently
available provide valuable information on the course of oxidative
metabolism of this type, which in turn permits the rational design of
deuterated compounds of the formula I with improved stability through
resistance to such oxidative metabolism. Significant improvements in the
pharmacokinetic profiles of compounds of the formula I are thereby
obtained, and can be expressed quantitatively in terms of increases in
the in vivo half-life (t/2), concentration at maximum therapeutic effect
(Cmax), area under the dose response curve (AUC), and F; and in
terms of reduced clearance, dose and materials costs.

[0062] The following is intended to illustrate the above: a compound of
the formula I which has multiple potential sites of attack for oxidative
metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded
to a nitrogen atom, is prepared as a series of analogues in which various
combinations of hydrogen atoms are replaced by deuterium atoms, so that
some, most or all of these hydrogen atoms have been replaced by deuterium
atoms. Half-life determinations enable favorable and accurate
determination of the extent of the extent to which the improvement in
resistance to oxidative metabolism has improved. In this way, it is
determined that the half-life of the parent compound can be extended by
up to 100% as the result of deuterium-hydrogen exchange of this type.

[0063] Deuterium-hydrogen exchange in a compound of the formula I can also
be used to achieve a favorable modification of the metabolite spectrum of
the starting compound in order to diminish or eliminate undesired toxic
metabolites. For example, if a toxic metabolite arises through oxidative
carbon-hydrogen (C--H) bond cleavage, it can reasonably be assumed that
the deuterated analogue will greatly diminish or eliminate production of
the unwanted metabolite, even if the particular oxidation is not a
rate-determining step. Further information on the state of the art with
respect to deuterium-hydrogen exchange may be found, for example in
Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org.
Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,
Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.
Carcinogenesis 16(4), 683-688, 1993.

[0064] As used herein, the term "modulator" is defined as a compound that
binds to and/or inhibits the target with measurable affinity. In certain
embodiments, a modulator has an IC50 and/or binding constant of less
about 50 μM, less than about 1 μM, less than about 500 nM, less
than about 100 nM, or less than about 10 nM.

[0065] The terms "measurable affinity" and "measurably inhibit," as used
herein, means a measurable change in IRAK activity between a sample
comprising a compound of the present invention, or composition thereof,
and IRAK, and an equivalent sample comprising IRAK, in the absence of
said compound, or composition thereof.

[0066] Combinations of substituents and variables envisioned by this
invention are only those that result in the formation of stable
compounds. The term "stable", as used herein, refers to compounds which
possess stability sufficient to allow manufacture and which maintains the
integrity of the compound for a sufficient period of time to be useful
for the purposes detailed herein (e.g., therapeutic or prophylactic
administration to a subject).

[0067] The recitation of a listing of chemical groups in any definition of
a variable herein includes definitions of that variable as any single
group or combination of listed groups. The recitation of an embodiment
for a variable herein includes that embodiment as any single embodiment
or in combination with any other embodiments or portions thereof.

3. Description of Exemplary Compounds

[0068] According to one aspect, the present invention provides a compound
of formula I,

##STR00006##

or a pharmaceutically acceptable salt thereof, wherein:

[0069] X is CR or
N;

[0070] A is O, S, SO2, SO, --NRC(O), --NRSO2, or N(R); or A
is absent;

[0072]
when A is --NRC(O), --NRSO2, or N(R); then R and R3, together
with the atoms to which each is attached, may form a 3-7 membered
heterocylic ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur; each of which is optionally substituted;

[0073] X' is CR or N;

[0074] Ring Z is a 3-7 membered heterocylic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; each of which is optionally
substituted;

[0080] each R is independently hydrogen,
C1-6 aliphatic, C3-10 aryl, a 3-8 membered saturated or
partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring
having 1-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur; each
of which is optionally substituted; or

[0081] two R groups on the same
atom are taken together with the atom to which they are attached to form
a C3-10 aryl, a 3-8 membered saturated or partially unsaturated
carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; each of which is optionally
substituted;

[0082] wherein when X is N and A is absent, then R3 is
not H.

[0083] In certain embodiments, X is CR. In certain embodiments, X is CH.
In certain embodiments, X is N.

[0084] In certain embodiments, A is O or N(R). In certain embodiments, A
is O. In certain embodiments, A is N(R). In a further embodiment, A is NH
or N-Me.

[0085] In certain embodiments, A is absent.

[0086] In certain embodiments, A is absent when R3 is alkyl or
substituted alkyl.

[0087] In certain embodiments, A is N(R), and the ring formed by R and
R3 is a 3-7 membered heterocylic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; each of which is optionally
substituted.

[0095] In certain embodiments, X' is CR. In certain embodiments, X' is CH.
In certain embodiments, X' is N.

[0096] In certain embodiments, Ring Z is a 3-7 membered heterocylic ring
having 1-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur; each
of which is optionally substituted;

[0113] In certain embodiments, Rb is absent. In certain embodiments,
Rb is an optionally substituted C1-6 aliphatic, C(O)NR2,
or COR.

[0114] In certain embodiments, Ring Y is

##STR00024##

[0115] In certain embodiments, each of Ring Z, Ring Y, R1, R2,
R3, Ra, Rb, A, X, and X', is as defined above and described in
embodiments, classes and subclasses above and herein, singly or in
combination.

[0116] In certain embodiments, the present invention provides a compound
of formula I-a,

##STR00025##

or a pharmaceutically acceptable salt thereof, wherein each of Ring Y,
R2, R3, Ra, Rb, A, X, and X', is as defined above and
described in embodiments, classes and subclasses above and herein, singly
or in combination.

[0117] In certain embodiments, the present invention provides a compound
of formula I-b,

##STR00026##

or a pharmaceutically acceptable salt thereof, wherein each of Ring Y,
R2, R3, Ra, Rb, A, and X', is as defined above and
described in embodiments, classes and subclasses above and herein, singly
or in combination.

[0118] In certain embodiments, the present invention provides a compound
of formula I-c,

##STR00027##

or a pharmaceutically acceptable salt thereof, wherein each of Ring Y,
R2, R3, Ra, Rb, A, and X', and m is as defined above
and described in embodiments, classes and subclasses above and herein,
singly or in combination.

[0119] In certain embodiments, the present invention provides a compound
of formula I-d,

##STR00028##

or a pharmaceutically acceptable salt thereof, wherein each of R2,
R3, A, and X', is as defined above and described in embodiments,
classes and subclasses above and herein, singly or in combination.

[0120] In certain embodiments, the present invention provides a compound
of formula I-e,

##STR00029##

or a pharmaceutically acceptable salt thereof, wherein each of R2,
R3, A, and X', is as defined above and described in embodiments,
classes and subclasses above and herein, singly or in combination.

[0121] In certain embodiments, the present invention provides a compound
of formula I-f,

##STR00030##

or a pharmaceutically acceptable salt thereof, wherein each of R2,
R3, A, and X', is as defined above and described in embodiments,
classes and subclasses above and herein, singly or in combination.

[0122] In certain embodiments, the invention provides a compound selected
from Table 1:

[0123] In some embodiments, the present invention provides a compound
selected from those depicted above, or a pharmaceutically acceptable salt
thereof.

[0124] Various structural depictions may show a heteroatom without an
attached group, radical, charge, or counterion. Those of ordinary skill
in the art are aware that such depictions are meant to indicate that the
heteroatom is attached to hydrogen (e.g.,

##STR00321##

is understood to be

##STR00322##

[0125] In certain embodiments, the compounds of the invention were
synthesized in accordance with the schemes provided in the Examples
below.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

[0126] According to another embodiment, the invention provides a
composition comprising a compound of this invention or a pharmaceutically
acceptable derivative thereof and a pharmaceutically acceptable carrier,
adjuvant, or vehicle. The amount of compound in compositions of this
invention is such that is effective to measurably inhibit IRAK, or a
mutant thereof, in a biological sample or in a patient. In certain
embodiments, the amount of compound in compositions of this invention is
such that is effective to measurably inhibit IRAK, or a mutant thereof,
in a biological sample or in a patient. In certain embodiments, a
composition of this invention is formulated for administration to a
patient in need of such composition.

[0127] The term "patient" or "subject", as used herein, means an animal,
preferably a mammal, and most preferably a human.

[0129] A "pharmaceutically acceptable derivative" means any non-toxic
salt, ester, salt of an ester or other derivative of a compound of this
invention that, upon administration to a recipient, is capable of
providing, either directly or indirectly, a compound of this invention or
an inhibitorily active metabolite or residue thereof.

[0131] The term "parenteral" as used herein includes subcutaneous,
intravenous, intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional and intracranial
injection or infusion techniques. Preferably, the compositions are
administered orally, intraperitoneally or intravenously. Sterile
injectable forms of the compositions of this invention include aqueous or
oleaginous suspension. These suspensions are formulated according to
techniques known in the art using suitable dispersing or wetting agents
and suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that are
employed are water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils are conventionally employed as
a solvent or suspending medium.

[0132] For this purpose, any bland fixed oil employed includes synthetic
mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride
derivatives are useful in the preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions or
suspensions also contain a long-chain alcohol diluent or dispersant, such
as carboxymethyl cellulose or similar dispersing agents that are commonly
used in the formulation of pharmaceutically acceptable dosage forms
including emulsions and suspensions. Other commonly used surfactants,
such as Tweens, Spans and other emulsifying agents or bioavailability
enhancers which are commonly used in the manufacture of pharmaceutically
acceptable solid, liquid, or other dosage forms are also be used for the
purposes of formulation.

[0133] Pharmaceutically acceptable compositions of this invention are
orally administered in any orally acceptable dosage form. Exemplary oral
dosage forms are capsules, tablets, aqueous suspensions or solutions. In
the case of tablets for oral use, carriers commonly used include lactose
and corn starch. Lubricating agents, such as magnesium stearate, are also
typically added. For oral administration in a capsule form, useful
diluents include lactose and dried cornstarch. When aqueous suspensions
are required for oral use, the active ingredient is combined with
emulsifying and suspending agents. If desired, certain sweetening,
flavoring or coloring agents are optionally also added.

[0134] Alternatively, pharmaceutically acceptable compositions of this
invention are administered in the form of suppositories for rectal
administration. These can be prepared by mixing the agent with a suitable
non-irritating excipient that is solid at room temperature but liquid at
rectal temperature and therefore will melt in the rectum to release the
drug. Such materials include cocoa butter, beeswax and polyethylene
glycols.

[0135] Pharmaceutically acceptable compositions of this invention are also
administered topically, especially when the target of treatment includes
areas or organs readily accessible by topical application, including
diseases of the eye, the skin, or the lower intestinal tract. Suitable
topical formulations are readily prepared for each of these areas or
organs.

[0136] Topical application for the lower intestinal tract can be effected
in a rectal suppository formulation (see above) or in a suitable enema
formulation. Topically-transdermal patches are also used.

[0137] For topical applications, provided pharmaceutically acceptable
compositions are formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Exemplary
carriers for topical administration of compounds of this are mineral oil,
liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water. Alternatively,
provided pharmaceutically acceptable compositions can be formulated in a
suitable lotion or cream containing the active components suspended or
dissolved in one or more pharmaceutically acceptable carriers. Suitable
carriers include, but are not limited to, mineral oil, sorbitan
monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,
2-octyldodecanol, benzyl alcohol and water.

[0138] Pharmaceutically acceptable compositions of this invention are
optionally administered by nasal aerosol or inhalation. Such compositions
are prepared according to techniques well-known in the art of
pharmaceutical formulation and are prepared as solutions in saline,
employing benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, fluorocarbons, and/or other
conventional solubilizing or dispersing agents.

[0139] Most preferably, pharmaceutically acceptable compositions of this
invention are formulated for oral administration. Such formulations may
be administered with or without food. In some embodiments,
pharmaceutically acceptable compositions of this invention are
administered without food. In other embodiments, pharmaceutically
acceptable compositions of this invention are administered with food.

[0140] The amount of compounds of the present invention that are
optionally combined with the carrier materials to produce a composition
in a single dosage form will vary depending upon the host treated, the
particular mode of administration. Preferably, provided compositions
should be formulated so that a dosage of between 0.01-100 mg/kg body
weight/day of the compound can be administered to a patient receiving
these compositions.

[0141] It should also be understood that a specific dosage and treatment
regimen for any particular patient will depend upon a variety of factors,
including the activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of administration, rate of
excretion, drug combination, and the judgment of the treating physician
and the severity of the particular disease being treated. The amount of a
compound of the present invention in the composition will also depend
upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

[0142] The present invention furthermore relates to a method for treating
a subject suffering from an IRAK related disorder, comprising
administering to said subject an effective amount of a compound of
formula I and related formulae.

[0143] The present invention preferably relates to a method, wherein the
IRAK associated disorder is an autoimmune disorder or condition
associated with an overactive immune response or cancer. The present
invention furthermore relates to a method of treating a subject suffering
from an immunoregulatory abnomality, comprising administering to said
subject a compound of formula (I), and related formulae in an amount that
is effective for treating said immunoregulatory abnormality.

[0150] In various embodiments, compounds of formula (I), and related
formulae exhibit a IC50 for the binding to IRAK of less than about 5
μM, preferably less than about 1 μM and even more preferably less
than about 0.100 μM.

[0151] The method of the invention can be performed either in-vitro or
in-vivo. The susceptibility of a particular cell to treatment with the
compounds according to the invention can be particularly determined by
in-vitro tests, whether in the course of research or clinical
application. Typically, a culture of the cell is combined with a compound
according to the invention at various concentrations for a period of time
which is sufficient to allow the active agents to inhibit IRAK activity,
usually between about one hour and one week. In-vitro treatment can be
carried out using cultivated cells from a biopsy sample or cell line.

[0152] The host or patient can belong to any mammalian species, for
example a primate species, particularly humans; rodents, including mice,
rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models
are of interest for experimental investigations, providing a model for
treatment of human disease.

[0153] For identification of a signal transduction pathway and for
detection of interactions between various signal transduction pathways,
various scientists have developed suitable models or model systems, for
example cell culture models and models of transgenic animals. For the
determination of certain stages in the signal transduction cascade,
interacting compounds can be utilized in order to modulate the signal.
The compounds according to the invention can also be used as reagents for
testing IRAK-dependent signal transduction pathways in animals and/or
cell culture models or in the clinical diseases mentioned in this
application.

[0154] Moreover, the subsequent teaching of the present specification
concerning the use of the compounds according to formula (I) and its
derivatives for the production of a medicament for the prophylactic or
therapeutic treatment and/or monitoring is considered as valid and
applicable without restrictions to the use of the compound for the
inhibition of IRAK activity if expedient.

[0155] The invention also relates to the use of compounds according to
formula (I) and/or physiologically acceptable salts thereof for the
prophylactic or therapeutic treatment and/or monitoring of diseases that
are caused, mediated and/or propagated by IRAK activity. Furthermore, the
invention relates to the use of compounds according to formula (I) and/or
physiologically acceptable salts thereof for the production of a
medicament for the prophylactic or therapeutic treatment and/or
monitoring of diseases that are caused, mediated and/or propagated by
IRAK activity. In certain embodiments, the invention provides the use of
a compound according to formula I or physiologically acceptable salts
thereof, for the production of a medicament for the prophylactic or
therapeutic treatment of a IRAK-mediated disorder.

[0156] Compounds of formula (I) and/or a physiologically acceptable salt
thereof can furthermore be employed as intermediate for the preparation
of further medicament active ingredients. The medicament is preferably
prepared in a non-chemical manner, e.g. by combining the active
ingredient with at least one solid, fluid and/or semi-fluid carrier or
excipient, and optionally in conjunction with a single or more other
active substances in an appropriate dosage form.

[0157] The compounds of formula (I) according to the invention can be
administered before or following an onset of disease once or several
times acting as therapy. The aforementioned compounds and medical
products of the inventive use are particularly used for the therapeutic
treatment. A therapeutically relevant effect relieves to some extent one
or more symptoms of a disorder, or returns to normality, either partially
or completely, one or more physiological or biochemical parameters
associated with or causative of a disease or pathological condition.
Monitoring is considered as a kind of treatment provided that the
compounds are administered in distinct intervals, e.g. in order to boost
the response and eradicate the pathogens and/or symptoms of the disease
completely. Either the identical compound or different compounds can be
applied. The methods of the invention can also be used to reduce the
likelihood of developing a disorder or even prevent the initiation of
disorders associated with IRAK activity in advance or to treat the
arising and continuing symptoms.

[0158] In the meaning of the invention, prophylactic treatment is
advisable if the subject possesses any preconditions for the
aforementioned physiological or pathological conditions, such as a
familial disposition, a genetic defect, or a previously incurred disease.

[0159] The invention furthermore relates to a medicament comprising at
least one compound according to the invention and/or pharmaceutically
usable derivatives, salts, solvates and stereoisomers thereof, including
mixtures thereof in all ratios. In certain embodiments, the invention
relates to a medicament comprising at least one compound according to the
invention and/or physiologically acceptable salts thereof.

[0160] A "medicament" in the meaning of the invention is any agent in the
field of medicine, which comprises one or more compounds of formula (I)
or preparations thereof (e.g. a pharmaceutical composition or
pharmaceutical formulation) and can be used in prophylaxis, therapy,
follow-up or aftercare of patients who suffer from diseases, which are
associated with IRAK activity, in such a way that a pathogenic
modification of their overall condition or of the condition of particular
regions of the organism could establish at least temporarily.

[0161] In various embodiments, the active ingredient may be administered
alone or in combination with other treatments. A synergistic effect may
be achieved by using more than one compound in the pharmaceutical
composition, i.e. the compound of formula (I) is combined with at least
another agent as active ingredient, which is either another compound of
formula (I) or a compound of different structural scaffold. The active
ingredients can be used either simultaneously or sequentially.

[0162] Included herein are methods of treatment in which at least one
chemical entity provided herein is administered in combination with an
anti-inflammatory agent. Anti-inflammatory agents include but are not
limited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzyme
inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis
factor (TNF) antagonists, immunosuppressants and methotrexate.

[0164] In some embodiments, the anti-inflammatory agent is a salicylate.
Salicylates include by are not limited to acetylsalicylic acid or
aspirin, sodium salicylate, and choline and magnesium salicylates.

[0165] The anti-inflammatory agent may also be a corticosteroid. For
example, the corticosteroid may be cortisone, dexamethasone,
methylprednisolone, prednisolone, prednisolone sodium phosphate, or
prednisone.

[0166] In additional embodiments the anti-inflammatory agent is a gold
compound such as gold sodium thiomalate or auranofin.

[0167] The invention also includes embodiments in which the
anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate
reductase inhibitor, such as methotrexate or a dihydroorotate
dehydrogenase inhibitor, such as leflunomide.

[0168] Other embodiments of the invention pertain to combinations in which
at least one anti-inflammatory compound is an anti-monoclonal antibody
(such as eculizumab or pexelizumab), a TNF antagonist, such as
entanercept, or infliximab, which is an anti-TNF alpha monoclonal
antibody.

[0169] Still other embodiments of the invention pertain to combinations in
which at least one active agent is an immunosuppressant compound such as
an immunosuppressant compound chosen from methotrexate, leflunomide,
cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

[0170] The disclosed compounds of the formula I can be administered in
combination with other known therapeutic agents, including anticancer
agents. As used here, the term "anticancer agent" relates to any agent
which is administered to a patient with cancer for the purposes of
treating the cancer.

[0171] The anti-cancer treatment defined above may be applied as a
monotherapy or may involve, in addition to the herein disclosed compounds
of formula I, conventional surgery or radiotherapy or medicinal therapy.
Such medicinal therapy, e.g. a chemotherapy or a targeted therapy, may
include one or more, but preferably one, of the following anti-tumor
agents:

[0172] In another aspect, the invention provides for a kit consisting of
separate packs of an effective amount of a compound according to the
invention and/or pharmaceutically acceptable salts, derivatives, solvates
and stereoisomers thereof, including mixtures thereof in all ratios, and
optionally, an effective amount of a further active ingredient. The kit
comprises suitable containers, such as boxes, individual bottles, bags or
ampoules. The kit may, for example, comprise separate ampoules, each
containing an effective amount of a compound according to the invention
and/or pharmaceutically acceptable salts, derivatives, solvates and
stereoisomers thereof, including mixtures thereof in all ratios, and an
effective amount of a further active ingredient in dissolved or
lyophilized form.

[0173] As used herein, the terms "treatment," "treat," and "treating"
refer to reversing, alleviating, delaying the onset of, or inhibiting the
progress of a disease or disorder, or one or more symptoms thereof, as
described herein. In some embodiments, treatment is administered after
one or more symptoms have developed. In other embodiments, treatment is
administered in the absence of symptoms. For example, treatment is
administered to a susceptible individual prior to the onset of symptoms
(e.g., in light of a history of symptoms and/or in light of genetic or
other susceptibility factors). Treatment is also continued after symptoms
have resolved, for example to prevent or delay their recurrence.

[0174] The compounds and compositions, according to the method of the
present invention, are administered using any amount and any route of
administration effective for treating or lessening the severity of a
disorder provided above. The exact amount required will vary from subject
to subject, depending on the species, age, and general condition of the
subject, the severity of the infection, the particular agent, its mode of
administration, and the like. Compounds of the invention are preferably
formulated in dosage unit form for ease of administration and uniformity
of dosage. The expression "dosage unit form" as used herein refers to a
physically discrete unit of agent appropriate for the patient to be
treated. It will be understood, however, that the total daily usage of
the compounds and compositions of the present invention will be decided
by the attending physician within the scope of sound medical judgment.
The specific effective dose level for any particular patient or organism
will depend upon a variety of factors including the disorder being
treated and the severity of the disorder; the activity of the specific
compound employed; the specific composition employed; the age, body
weight, general health, sex and diet of the patient; the time of
administration, route of administration, and rate of excretion of the
specific compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed, and like
factors well known in the medical arts.

[0175] Pharmaceutically acceptable compositions of this invention can be
administered to humans and other animals orally, rectally, parenterally,
intracisternally, intravaginally, intraperitoneally, topically (as by
powders, ointments, or drops), bucally, as an oral or nasal spray, or the
like, depending on the severity of the infection being treated. In
certain embodiments, the compounds of the invention are administered
orally or parenterally at dosage levels of about 0.01 mg/kg to about 100
mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.

[0176] In certain embodiments, a therapeutically effective amount of a
compound of the formula (I), and related formulae and of the other active
ingredient depends on a number of factors, including, for example, the
age and weight of the animal, the precise disease condition which
requires treatment, and its severity, the nature of the formulation and
the method of administration, and is ultimately determined by the
treating doctor or vet. However, an effective amount of a compound is
generally in the range from 0.1 to 100 mg/kg of body weight of the
recipient (mammal) per day and particularly typically in the range from 1
to 10 mg/kg of body weight per day. Thus, the actual amount per day for
an adult mammal weighing 70 kg is usually between 70 and 700 mg, where
this amount can be administered as an individual dose per day or usually
in a series of part-doses (such as, for example, two, three, four, five
or six) per day, so that the total daily dose is the same. An effective
amount of a salt or solvate or of a physiologically functional derivative
thereof can be determined as the fraction of the effective amount of the
compound per se.

[0177] In certain embodiments, the pharmaceutical formulations can be
administered in the form of dosage units, which comprise a predetermined
amount of active ingredient per dosage unit. Such a unit can comprise,
for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly
preferably 5 mg to 100 mg, of a compound according to the invention,
depending on the disease condition treated, the method of administration
and the age, weight and condition of the patient, or pharmaceutical
formulations can be administered in the form of dosage units which
comprise a predetermined amount of active ingredient per dosage unit.
Preferred dosage unit formulations are those which comprise a daily dose
or part-dose, as indicated above, or a corresponding fraction thereof of
an active ingredient. Furthermore, pharmaceutical formulations of this
type can be prepared using a process, which is generally known in the
pharmaceutical art.

[0179] Injectable preparations, for example, sterile injectable aqueous or
oleaginous suspensions are formulated according to the known art using
suitable dispersing or wetting agents and suspending agents. The sterile
injectable preparation are also a sterile injectable solution, suspension
or emulsion in a nontoxic parenterally acceptable diluent or solvent, for
example, as a solution in 1,3-butanediol. Among the acceptable vehicles
and solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid are used in the
preparation of injectables.

[0180] Injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which can be
dissolved or dispersed in sterile water or other sterile injectable
medium prior to use.

[0181] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the compound
from subcutaneous or intramuscular injection. This is accomplished by the
use of a liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the compound then depends
upon its rate of dissolution that, in turn, may depend upon crystal size
and crystalline form. Alternatively, delayed absorption of a parenterally
administered compound form is accomplished by dissolving or suspending
the compound in an oil vehicle. Injectable depot forms are made by
forming microencapsule matrices of the compound in biodegradable polymers
such as polylactide-polyglycolide. Depending upon the ratio of compound
to polymer and the nature of the particular polymer employed, the rate of
compound release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot injectable
formulations are also prepared by entrapping the compound in liposomes or
microemulsions that are compatible with body tissues.

[0182] Compositions for rectal or vaginal administration are preferably
suppositories which can be prepared by mixing the compounds of this
invention with suitable non-irritating excipients or carriers such as
cocoa butter, polyethylene glycol or a suppository wax which are solid at
ambient temperature but liquid at body temperature and therefore melt in
the rectum or vaginal cavity and release the active compound.

[0184] Solid compositions of a similar type are also employed as fillers
in soft and hard-filled gelatin capsules using such excipients as lactose
or milk sugar as well as high molecular weight polyethylene glycols and
the like. The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as enteric
coatings and other coatings well known in the pharmaceutical formulating
art. They optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract, optionally, in
a delayed manner. Examples of embedding compositions that can be used
include polymeric substances and waxes. Solid compositions of a similar
type are also employed as fillers in soft and hard-filled gelatin
capsules using such excipients as lactose or milk sugar as well as high
molecular weight polethylene glycols and the like.

[0185] The active compounds can also be in micro-encapsulated form with
one or more excipients as noted above. The solid dosage forms of tablets,
dragees, capsules, pills, and granules can be prepared with coatings and
shells such as enteric coatings, release controlling coatings and other
coatings well known in the pharmaceutical formulating art. In such solid
dosage forms the active compound may be admixed with at least one inert
diluent such as sucrose, lactose or starch. Such dosage forms also
comprise, as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such a
magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms optionally also comprise
buffering agents. They optionally contain opacifying agents and can also
be of a composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract, optionally, in
a delayed manner. Examples of embedding compositions that can be used
include polymeric substances and waxes.

[0186] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams, lotions,
gels, powders, solutions, sprays, inhalants or patches. The active
component is admixed under sterile conditions with a pharmaceutically
acceptable carrier and any needed preservatives or buffers as required.
Ophthalmic formulation, ear drops, and eye drops are also contemplated as
being within the scope of this invention. Additionally, the present
invention contemplates the use of transdermal patches, which have the
added advantage of providing controlled delivery of a compound to the
body. Such dosage forms can be made by dissolving or dispensing the
compound in the proper medium. Absorption enhancers can also be used to
increase the flux of the compound across the skin. The rate can be
controlled by either providing a rate controlling membrane or by
dispersing the compound in a polymer matrix or gel.

[0187] According to one embodiment, the invention relates to a method of
inhibiting IRAK activity in a biological sample comprising the step of
contacting said biological sample with a compound of this invention, or a
composition comprising said compound.

[0188] According to another embodiment, the invention relates to a method
of inhibiting IRAK, or a mutant thereof, activity in a biological sample
in a positive manner, comprising the step of contacting said biological
sample with a compound of this invention, or a composition comprising
said compound.

[0189] The compounds of the invention are useful in-vitro as unique tools
for understanding the biological role of IRAK, including the evaluation
of the many factors thought to influence, and be influenced by, the
production of IRAK and the interaction of IRAK. The present compounds are
also useful in the development of other compounds that interact with IRAK
since the present compounds provide important structure-activity
relationship (SAR) information that facilitate that development.
Compounds of the present invention that bind to IRAK can be used as
reagents for detecting IRAK in living cells, fixed cells, in biological
fluids, in tissue homogenates, in purified, natural biological materials,
etc. For example, by labeling such compounds, one can identify cells
expressing IRAK. In addition, based on their ability to bind IRAK,
compounds of the present invention can be used in in-situ staining, FACS
(fluorescence-activated cell sorting), sodium dodecyl sulfate
polyacrylamide gel electrophoresis (SDS-PAGE), ELISA (enzyme-linked
immunoadsorptive assay), etc., enzyme purification, or in purifying cells
expressing IRAK inside permeabilized cells. The compounds of the
invention can also be utilized as commercial research reagents for
various medical research and diagnostic uses. Such uses can include but
are not limited to: use as a calibration standard for quantifying the
activities of candidate IRAK inhibitors in a variety of functional
assays; use as blocking reagents in random compound screening, i.e. in
looking for new families of IRAK ligands, the compounds can be used to
block recovery of the presently claimed IRAK compounds; use in the
co-crystallization with IRAK enzyme, i.e. the compounds of the present
invention will allow formation of crystals of the compound bound to IRAK,
enabling the determination of enzyme/compound structure by x-ray
crystallography; other research and diagnostic applications, wherein IRAK
is preferably activated or such activation is conveniently calibrated
against a known quantity of an IRAK inhibitor, etc.; use in assays as
probes for determining the expression of IRAK in cells; and developing
assays for detecting compounds which bind to the same site as the IRAK
binding ligands.

[0190] The compounds of the invention can be applied either themselves
and/or in combination with physical measurements for diagnostics of
treatment effectiveness. Pharmaceutical compositions containing said
compounds and the use of said compounds to treat IRAK-mediated conditions
is a promising, novel approach for a broad spectrum of therapies causing
a direct and immediate improvement in the state of health, whether in
human or in animal. The orally bioavailable and active new chemical
entities of the invention improve convenience for patients and compliance
for physicians.

[0191] The compounds of formula (I), their salts, isomers, tautomers,
enantiomeric forms, diastereomers, racemates, derivatives, prodrugs
and/or metabolites are characterized by a high specificity and stability,
low manufacturing costs and convenient handling. These features form the
basis for a reproducible action, wherein the lack of cross-reactivity is
included, and for a reliable and safe interaction with the target
structure.

[0192] The term "biological sample", as used herein, includes, without
limitation, cell cultures or extracts thereof; biopsied material obtained
from a mammal or extracts thereof; and blood, saliva, urine, feces,
semen, tears, or other body fluids or extracts thereof.

[0193] Modulation of IRAK, or a mutant thereof, activity in a biological
sample is useful for a variety of purposes that are known to one of skill
in the art. Examples of such purposes include, but are not limited to,
blood transfusion, organ transplantation, biological specimen storage,
and biological assays.

EXEMPLIFICATION

[0194] As depicted in the Examples below, in certain exemplary
embodiments, compounds are prepared according to the following general
procedures. It will be appreciated that, although the general methods
depict the synthesis of certain compounds of the present invention, the
following general methods, and other methods known to one of ordinary
skill in the art, can be applied to all compounds and subclasses and
species of each of these compounds, as described herein.

[0195] The symbols and conventions used in the following descriptions of
processes, schemes, and examples are consistent with those used in the
contemporary scientific literature, for example, the Journal of the
American Chemical Society or the Journal of Biological Chemistry.

[0197] All reactions were conducted at room temperature unless otherwise
noted. All compounds of the present invention were synthesiszed by
processes developed by the inventors. 1H-NMR spectra were acquired
on a Bruker Avance III 400 or a Bruker DPX-300 MHz. Chemical shifts are
expressed in parts per million (ppm, δ units). Coupling constants
are in units of hertz (Hz). Splitting patterns describe apparent
multiplicities and are designated as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), qt (quintuplet) or br (broad).

[0203] In general, the compounds according to Formula (I) and related
formulae of this invention can be prepared from readily available
starting materials. If such starting materials are not commercially
available, they may be prepared by standard synthetic techniques. In
general, the synthesis pathways for any individual compound of Formula
(I) and related formulae will depend on the specific substituents of each
molecule, such factors being appreciated by those of ordinary skilled in
the art. The following general methods and procedures described
hereinafter in the examples may be employed to prepare compounds of
Formula (I) and related formulae. Reaction conditions depicted in the
following schemes, such as temperatures, solvents, or co-reagents, are
given as examples only and are not restrictive. It will be appreciated
that where typical or preferred experimental conditions (i.e. reaction
temperatures, time, moles of reagents, solvents etc.) are given, other
experimental conditions can also be used unless otherwise stated. Optimum
reaction conditions may vary with the particular reactants or solvents
used, but such conditions can be determined by the person skilled in the
art, using routine optimisation procedures. For all the protection and
deprotection methods, see Philip J. Kocienski, in "Protecting Groups",
Georg Thieme Verlag Stuttgart, N.Y., 1994 and, Theodora W. Greene and
Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley
Interscience, 3rd Edition 1999.

[0302] Pd/C (253 mg, 0.24 mmol, 0.10 eq.) was added to a solution of
benzyl N-[(1S,2S,3S)-3-[[(tert-butoxy)carbonyl](methyl)amino]-2-hydroxycy-
clohexyl]carbamate (1 g, 2.38 mmol, 1.00 eq.) in MeOH (4 mL) maintained
under nitrogen atmosphere. The mixture was then hydrogenated at room
temperature for 16 hours using a hydrogen balloon. The solids were
filtered out and the resulting mixture was concentrated under vacuum to
afford the tittle compound as a light yellow solid (630 mg, 98%).

[0308] The title compound was obtained following the procedure described
for intermediate 39 from tert-butyl
N-(5,5-difluoropiperidin-3-yl)carbamate (500 mg, 2.01 mmol, 0.93 eq.) as
a white solid (460 mg, 37%).

[0312] A solution of benzyl N-(cyclohex-2-en-1-yl)carbamate (400 mg, 1.56
mmol, 1.00 eq., 90%), sodium bicarbonate (267 mg, 3.11 mmol, 2.00 eq.,
98%), and m-CPBA (549 mg, 3.12 mmol, 2.00 eq., 98%) in DCM (25 mL) was
stirred for 3 h at 20° C. The reaction was then quenched by the
addition of 15 mL of Na2SO3 and diluted with 30 mL of water. It
was then extracted with DCM (3×15 mL). Combined organic layers were
concentrated under vacuum and purified by flash chromatography on silica
(EA/PE, 1:5) to give the title compound as a brown solid.

[0322] A solution of (1R)-1-phenylethan-1-amine (2.375 g, 18.62 mmol, 1.30
eq., 95%) in DCM (12 mL) was cooled to 0° C. and treated with
trimethylaluminium (11 mL, 1.20 eq., 2M in toluene) under nitrogen
atmosphere. It was stirred for 1 h before the addition of a solution of
(1R,6R)-2,2-difluoro-7-oxabicyclo[4.1.0]heptane (racemic, relative
stereochemistry, 2.260 g, 14.32 mmol, 1.00 eq.) in DCM (50 mL). The
resulting solution was stirred for 2 days at RT. The reaction was then
quenched by the addition of NH4Cl aq. The aqueous layer was
extracted with dichloromethane and the combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, filtrated and
concentrated under vacuum. Purification by flash chromatography on silica
(MTBE/petroleum ether, 1:10) afforded the title compound (first eluting
isomer) as a white solid (1.36 g, 33%).

[0326] The title compound was obtained following the procedure described
for intermediate 39 from (1S,6R)-6-amino-2,2-difluorocyclohexan-1-ol (200
mg, 1.19 mmol, 1.00 eq.) as a yellow solid (451 mg, 87%).

[0328] The title compound was obtained following the procedure described
for intermediate 40 from
(1S,6R)-6-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2,2-difluorocyclohexan--
1-ol (451 mg, 1.04 mmol, 1.00 eq.) as a yellow solid (208 mg, 58%).

[0330] A solution of
2,2,2-trichloro-N-[(1S,2S,3R)-2,3-dihydroxycycloheptyl]acetamide
(racemic--relative stereochemistry, prepared as described in JOC, 2002, p
7946-7956, 10 mg, 0.03 mmol, 1.00 eq.), 2,2-dimethoxypropane (7 mg, 0.06
mmol, 2.06 eq.) and TsOH (0.5 mg, 0.09 eq.) in Acetone (1 mL) was stirred
at RT for 16 h. The reaction mixture was then concentrated under reduced
pressure and the residue was redissolved in DCM. The organic layer was
washed with sat. NaHCO3, brine, dried over anhydrous magnesium
sulfate, filtered and concentrated to afford the title compound which was
used directly in the next step.

[0332] NaBH4 (71 mg, 1.78 mmol, 5.04 eq.) was added portionwise to a
solution of
N-[(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-yl]-2,2,-
2-trichloroacetamide (racemic, 130 mg, 0.35 mmol, 1.00 eq.) in ethanol (10
mL) maintained at 0° C. The resulting solution was then stirred
for 16 h at 40° C. The reaction was quenched by the addition of a
solution of hydrogen chloride (1M). The mixture was finally concentrated
under reduced pressure to afford the title compound as a white solid (140
mg).

[0348] The title compound was obtained following the procedure described
for intermediate 39 from cyclohept-2-en-1-amine (650 mg, 2.92 mmol, 1.02
eq.) as a yellow oil (460 mg, 48%). LC/MS: [M+H]+ Calc. 302.0. found
302.0.

[0455] The title compound was obtained following the procedure described
for example 28 from
2-[(3aR,4S,7aS)-2,2-dimethylhexahydro-1,3-benzodioxol-4-yl]-1H-isoindole--
1,3(2H)-dione (prepared as described in WO 2010017051). LC/MS: 486.3
(M+H).

[0482] A solution of conc. HCl (0.75 mL, 24.68 mmol, 62 eq.) in MeOH (1
mL) was added dropwise to a solution of
N-[(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-yl]-5-(1-
-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-
-amine (220 mg, 0.40 mmol, 1.00 eq.) in MeOH (2 mL) maintained at
0° C. The resulting solution was stirred for 16 h at RT. The pH
value of the solution was adjusted to 8 by addition of ammonia. The
reaction mixture was concentrated under vacuum and purified by flash
chromatography (H2O:MeOH, 1:1) to afford the title compound as a
racemic mixture (130 mg). The two enantiomers were separated by
Chiral-Prep-HPLC (Chiralpak IC, MeOH).

[0503] Kinase reaction was stopped by addition of EDTA. Supernatant was
discarded, plates were washed three times with 150 mM NaCl and
radioactivity was then measured in a Microbeta Trilux reader.

TLR7 Induced IL-6 in Human PBMC's

[0504] Human PBMC assay was used as one of the functional assay a to
monitor the activity of of IRAK1 and IRAK4 small molecule inhibitors on
TLR7 induced IL-6 secretion in human mononuclear cells (PBMC's). Human
PBMCs were prepared from buffy coats (whole blood enriched with
leukocytes and platelets) obtained from healthy volunteers used either
fresh or frozen are plated in assay media (RPMI+2% P/S/L-glu+10% HI-FBS)
and pre-treated with compounds in DMSO/media (range of concentrations
from 25 uM to 0.4 nM) or controls (0.25% DMSO) for 30 minutes at
37° C. in assay media. Following pre-treatment with IRAK1 and
IRAK4 inhibitors, PBMC's were stimulated with TLR7 specific ligand (2 uM)
overnight (16-18 hrs) at 37° C. After incubation supernatant was
transferred to 384 well PE AlphaPlate-384 (6005350) and IL-6 is
quantified using Perkin Elmer IL-6 Alpha LISA kit (AL223C). Plates were
read on an Envision® plate reader with Alpha Technology®.

[0506] (A) Injection vials: A solution of 100 g of an active ingredient
according to the invention and 5 g of disodium hydrogen phosphate in 3 l
of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid,
sterile filtered, transferred into injection vials, is lyophilized under
sterile conditions and is sealed under sterile conditions. Each injection
vial contains 5 mg of active ingredient.

[0507] (B) Suppositories: A mixture of 20 g of an active ingredient
according to the invention is melted with 100 g of soy lecithin and 1400
g of cocoa butter, is poured into moulds and is allowed to cool. Each
suppository contains 20 mg of active ingredient.

[0508] (C) Solution: A solution is prepared from 1 g of an active
ingredient according to the invention, 9.38 g of
NaH2PO4.2H2O, 28.48 g of Na2HPO4.12 H2O and
0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is
adjusted to 6.8, and the solution is made up to 1 l and sterilized by
irradiation. This solution could be used in the form of eye drops.

[0509] (D) Ointment: 500 mg of an active ingredient according to the
invention is mixed with 99.5 g of Vaseline under aseptic conditions.

[0510] (E) Tablets: A mixture of 1 kg of an active ingredient according to
the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc
and 0.1 kg of magnesium stearate is pressed to give tablets in a
conventional manner in such a way that each tablet contains 10 mg of
active ingredient.

[0511] (F) Coated tablets: Tablets are pressed analogously to Example E
and subsequently are coated in a conventional manner with a coating of
sucrose, potato starch, talc, tragacanth and dye.

[0512] (G) Capsules: 2 kg of an active ingredient according to the
invention are introduced into hard gelatin capsules in a conventional
manner in such a way that each capsule contains 20 mg of the active
ingredient.

[0513] (H) Ampoules: A solution of 1 kg of an active ingredient according
to the invention in 60 l of bidistilled water is sterile filtered,
transferred into ampoules, is lyophilized under sterile conditions and is
sealed under sterile conditions. Each ampoule contains 10 mg of active
ingredient.

[0514] (I) Inhalation spray: 14 g of an active ingredient according to the
invention are dissolved in 10 l of isotonic NaCl solution, and the
solution is transferred into commercially available spray containers with
a pump mechanism. The solution could be sprayed into the mouth or nose.
One spray shot (about 0.1 ml) corresponds to a dose of about 0.14 mg.

[0515] While a number of embodiments of this invention are described
herein, it is apparent that the basic examples may be altered to provide
other embodiments that utilize the compounds and methods of this
invention. Therefore, it will be appreciated that the scope of this
invention is to be defined by the appended claims rather than by the
specific embodiments that have been represented by way of example.